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The benefit and Risks of
Nutritional Supplements
Peiying Yang, Ph.D.
Department of General Oncology
The University of Texas M.D.
Anderson Cancer Center
Dietary Supplements
• Congress defined the term "dietary supplement"
in the Dietary Supplement Health and Education
Act (DSHEA)
“A dietary supplement is a product taken by
mouth that contains a "dietary ingredient"
intended to supplement the diet. The "dietary
ingredients" in these products may include:
vitamins, minerals, herbs or other
botanicals, amino acids, and substances such
as enzymes, organ tissues, glandulars, and
metabolites.”
FDA Regulations
• Dietary Supplement Health and Education Act
(DSHEA) was assigned into law by President Clinton
in 1994
• Create a new regulatory framework for the safety
and labeling of dietary supplements
• A firm is responsible for the safety of product
• Dietary supplements do not need approved by FDA
before they are marketed
• No health claim is allowed in the product
CAM Use in US in 2010
Dietary Supplement Use in
US
Guidance for Dietary Supplements
• Are dietary supplements safe?
• Benefit and Risk?
• How to buy the dietary supplements?
• What cautions need to be taken for
buying or taking the nutritional
supplement?
Benefits
• Augment the intake of nutrients that your
diet is lacking under normal or pathological
conditions
• Treat specific health conditions or risk
factors:
Folic acid used to reduce the spina bifida
Omega-3 used to reduce the
(Lovaza)
• Need more scientific evidence
triglycerides
Risk
• Toxicity
- Large dose
- wrong application
- Poor quality product
• Interaction with over counter or
prescription medications
• Not enough evidence for the safety
Omega-3 fatty acids – fish
and flaxseed oil
Metabolism of omega-6 and omega-3
fatty acids
Fish Oil and Omega-3 Fatty Acids
• Polyunsaturated fatty acids
• Three major omega-3 fatty acids:
- Alpha-linoleic acid (ALA, Flaxseed)
- Eicosapentaenoic acid (EPA, fish)
- Docosahexaenoic acid (DHA, fish)
• Most American diets provide at least 10
times more omega-6 than omega-3.
Dietary Source of Omega-3 Fatty
Acids
Food
Serving
omega-3 fatty acids
% DV
Density
Quality
Flax seeds
0.25 cups
7.0 g
156.4
17.6
Excellent
Walnuts C
0.25 cup
2.3 g
50.4
6.3
Very good
Chinook salmon, baked/broiled
4.0 oz-wt
2.1 g
46.4
3.6
Very good
Scallops, baked/broiled
4.0 oz-wt
1.1 g
24.4
3.3
Good
Soybeans, cooked
1 cup
1.0 g
22.9
1.6
Good
Halibut, baked/broiled
4.0 oz-wt
0.6 g
13.8
1.8
Good
Shrimp, steamed, boiled
4.0 oz-wt
0.4 g
8.2
1.5
Good
Snapper, baked
4.0 oz-wt
0.4 g
8.0
1.1
Good
Tofu, raw
4.0 oz-wt
0.4 g
8.0
1.9
Good
Winter squash
1 cup
0.3 g
7.6
1.9
Good
Tuna, yellowfin
4.0 oz-wt
0.3 g
7.3
0.9
-
Cod, baked
4.0 oz-wt
0.3 g
7.1
1.2
-
Kidney beans
1 cup
0.3 g
6.7
0.6
-
Note: Algae oils are the vegetarian source of DHA.
Flaxseed and Fish Oil Supplements
• Total of 136 products containing Flaxseed
powder or Flaxseed oil
• Fish oil:
- Fish oil in triglyceride form- Nordic
-
Fish oil in ethyl ester form – Lovaza
Fish oil in phospholipid form – Krill oil
• Ratio of EPA and DHA in fish oil
-
3:2 (menhaden oil, ultimate omega)
4:1 (EPA, Nordic Natural)
1:5 (DHA, Nordic Natural)
Natural
“Does fish oil (鱼油）provide a rationale
treatment strategy for cancer?”
Anti-inflammatory
Cardiovascular
protection
Fish oil
(n-3 fatty acids)
Immune
modulation
Anti-tumor ?
Augments
cytotoxic
effects of
chemother
apy
Challenges of Choosing the Right
Supplements
EPA/DHA 325:225
EPA/DHA 650:450
EPA/DHA 850:200
EPA/DHA 1060:274
1. Quality of products – Source of fish oil and contaminations
2. Right amount of total omega-3 fatty acids needed
3. Special ratio of EPA/DHA
4. Healthy and pathological conditions
5. USP certification? (Fish oil made by Kirkland Signature, Nutri Plus
or Nature Made)
Metabolism of AA and EPA to the
Prostaglandin Subfamily of Eicosanoids
EPA
AA
Cyclooxygenase
PGH2
PGF2 PGD2
PGH3
Specific
prostaglandin
synthesis
PGE2
PGE3
PGD3
PGF3
• Study suggested that PGE2 promote the proliferation,
invasion and metastasis of tumor; whereas PGE3 inhibits the
proliferation of various cancer cells.
Yang, P. et al, Journal of Lipid Research, 2004
Hypothesis
• Anti-tumor activity of fish oil n3 fatty acids is associated with
inhibition of PGE2 formation
and concomitant increased
formation of PGE3 in NSCLC
cells
COX-2
Percent Growth of Control Cells
siRNA 0.4 M
siRNA 0.2 M
120
Control
Transfected Control
Genetically deletion of COX-2 gene
reduced EPA elicited anti-proliferative
activity in A549 cells
Control siRNA
COX-2 siRNA
100
80
60
40
20
0
0
-actin
50
100
150
200
250
Concentration of EPA (M)
-Actin
Percent growth of control cells
COX-2
A549
shRNA
120
100
80
60
**/a
**
40
***
20
0
EPA ( M)
0
25
50
Control ShRNA
0
25
COX-2 ShRNA
50
The inhibitory effect of EPA or PGE3 in
A549 cells was mediated through
PI3kinase pathways
A549 cells
Akt
PGE2 (nM)
PGE 3 (nM)
0 10 100 1000 10 100 1000
Akt
-actin
pAkt
PGE2 (nM)
PGE3 (nM)
0 10 100 1000 10 100 1000
Akt
pAkt
-actin
EPA (µM)
---------------------0
pAkt
H1299
A549 cells
H1299 cells
Akt
pAkt
10
25
50
Fish Oil derived n-3 Fatty acid EPA inhibits proliferation of NSCLC
cells mediated through COX-2 pathways
120
A549 cells
H1299 cells
Percent growth of control cells
100
COX-1
COX-2
80
60
40
20
0
-Actin
PGE3 (ng/5 million cells)
1
10
***
8
A549 cells
H1299 cells
6
**
4
***
2
0
10
Concentration of EPA (M)
**
**
0
10
25
50
Concentration of EPA (M)
100
1000
Fish oil inhibited tumor growth in A549 xenograft
model but not H1299 model
A549 xengoraft
H1299 xengoraft
*
Soybean oil diet
Menhaden oil diet
Ratio of PGE3 over PGE2
250
*
400
200
0.6
Soybean oil diet
Menhaden oil diet
200
150
100
50
0
Flank Tumor
Shoulder Tumor
0.5
A549 Xenograft tissue
H1299 Xenograft tissue
0.4
0.3
0.2
0.1
0.0
0
Soybean oil group
Flank Tumor
Menhaden oil group
Shoulder Tumor
p38
P70S6K
PI3Kinase
Stat 3 (pS723)
Stat 3 (Y705)
0.3
Arbitrary Units
600
300
Tumor Weight (mg)
Tumor weight (mg)
800
0.2
*
0.1
0.0
Soybean oil
Menhaden oil
Fish oil and non-Hodgkin lymphoma
Arachidonic Acid Eicosapentaenoic acids
COX-2
PGE2
PGE3
Seven-transmembrane receptors (EP2 to EP4)
Adenylate cyclase
cAMP
PKA or cAMP binding protein
PI3kinase
EGFR
ERK
Cell proliferation, apoptosis and angiogenesis
Proposed mechanism of PGE2
and PGE3 mediated cell
proliferation and angiogenesis.
Ø Specific Aim 1: To identify the effect of EPA and DHA alone
or in combination on growth of human NHL cells BJAB (COX-2
over-expressing) and RAJi (COX-2 lacking) cells.
Ø Specific Aim 2: To examine eicosanoid metabolism in
human normal B cells and NHL cells after exposure to EPA and
DHA.
Ø Specific Aim 3: To evaluate the efficacy of EPA, DHA and
these two agents combined on tumor growth and eicosanoid
metabolism in mouse models of human NHL.
Ø Specific Aim 4: To determine the effect of PGE2 and PGE3
on cell proliferation, mobility and cAMP-PKA and PI3K/Akt
signaling pathways in human normal B cells and NHL cells.
Chemopreventive effect of fish oil derived EPA in
lung cancer
• To identify the relationship of COX-2 and EPA on lung tumor development
using urethane-treated wild-type and COX-2 deficient FVB mice, and Krastransgenic mice.
- EPA and Lovaza, an FDA approved fish oil product will be the study agents
- Anti-Inflammation and tumor development as the end points
- Eicosanoids, particularly PGE2, PGE3 and their metabolites as the biomarkers
• To determine the tumor growth-suppressing effects in vitro of different ratios
of PGE3:PGE2 and the mechanisms by which these effects occur. The effects
will be assessed in the COX-2 expressing or COX-2 null human lung cancer
cells.
• To identify the role of PGE2 receptors in the anti-proliferative effect of fish oilderived PGE3.
- Binding capacity of PGE2 and PGE3 to EP receptors
- Cell signaling of EP2 and EP4 receptors response to PGE2 and PGE3
- Chemopreventive effect on urethane-induced lung cancer in EP2 and EP4 knockout mice
Study agent:
A. 4 1-g gelatin capsules per day containing 2.2 g EPA and 240 mg
DHA (EPA: DHA; 9:1)
B. 7.5 ml liquid fish oil per day (2.2 g EPA and 500 mg DHA;
EPA:DHA; 4:1)
No special information was provided with respect to the type
of fish oils administered.
Expression of the Fat-1 gene diminishes prostate
cancer growth in vivo through enhancing apoptosis
and inhibiting GSK-3 beta phosphorylation
Is Flaxseed safe for someone
with breast cancer?
Flaxseed powder is a rich source
of lignans which has ability to
influence estrogen production and
metabolism
The effect of flaxseed and breast cancer
•
Reduced tumor growth and sensitises tamoxifen treatment of MCF7 xenograft model either at regular or high levels of circulating
estrogen (Truan JS, et al., Mol Nutr Food Res, 2010; Chen J, J Nutr, 2009)
•
Flaxseed powder decreased release of IL-1 derived from murine
stroma and microvessel density, suggesting inhibition of
angiogenesis in breast cancer.
•
Flaxseed oil (Pizzey Nutritionals, Canada) augmented tumorreducing effects of trastuzumab (primary drug for HER2 positive
patient) in HER2 overexpressing tumor (BT-474).
•
Flaxseed powder did not alter the estrogen metabolism in
postmenopausal women (Strugeon SR, et al., Nutr Cancer, 2010)
•
Flaxseed powder attenuated soy protein isolate induced breast
cancer development in MCF-7 bearing mice, suggesting soy protein
and flaxseed differentially modulate tumor markers and cell
signaling pathways (Power KA, et al., J Steroid Biochem Mol Biol, 2008)
•
Mechanistically, Flaxseed has ability to inhibit angiogenesis, IGF-1alpha, and
VEGF pathways.
•
The inhibitory effect of flaxseed on the growth and metastasis of
estrogen receptor negative human breast cancer xenograftsis
attributed to both its lignan and oil components.
Soy: another phytoestrogen
containing food
Structure of Estrodial and
Phytoestrogen in Soy
Genistein
Estrodial
Genistin
Soy Phytoestrogen and
Estrogen Receptors (ERs)
• Two estrogen receptors: ER and ER
• ER mediates the proliferative actions of estrogens;
whereas ER binds to ER and inhibits its action
• ER is expressed at a significantly higher level than ER
during early development and normal adult breast
• Levels of ER are higher than that of ER in breast tumor
• Genistein preferably binds to ER particularly when it is at
relatively lower dose (~5-8 nM), but it does have equal
binding capability to ER like estrodial.
• Genistein appears bind and activate ER in breast tumor
because it upregulates estrogen responsive genes, such as
pS2 and c-fos.
The Effect of Phytoestrogens and Other
Soy Products on the Growth of MCF-7
Xenograft Models
Plausible Mechanism of
Genistein
Results of Western Women Studies
1. No protective
effect
2. Almost
significantly
increased risk of
recurrence
among those not
taking tamoxifen
and having the
highest intake of
genistein and
daidzein
Total of 1954 patients were included in this study
Results of Chinese Women Studies
Significantly
reduced risk of
recurrence with
highest level of
isoflavones and
soy protein in
their diet
Total of 5042 breast cancer survivors
Challenges of Soy Studies
• Marked differences in the products used in
the studies;
-Whole soy foods (Chinese)
- Soy proteins (Western)
• Difference on the ages starting consuming
soy products
• The genetic difference between western and
Chinese with respect to absorption and
digestion of soy
• Other dietary components ingested
routinely
Plausible Conclusions
• Soy intake during childhood and
adolescence might provide lifelong
protection against breast cancer
• Reduction of risk of recurrence in
Asian women consuming soy
regularly
• Lifetime soy consumption at a
moderate level may prevent breast
cancer recurrence
Vitamin D
• Fat soluble vitamin or sunshine vitamin or a
hormone
• Structurally, it belongs to secosteroids
• Increasing the efficiency of intestinal calcium
and phosphate absorption for the
maintenance of the skeleton throughout life
• Deficiency of Vitamin D is linked to increased
risk for preeclampsia, multiple sclerosis,
rheumatoid arthritis, diabetes, heart disease,
dementia, deadly cancers.
Overview of source and function of Vitamin D
Holick, M., J Investigative Med, 2011
Synthesis of Vitamin D3 in Normal
Skin
UV light
9 am to 4 pm
7-hydroxycholeterol
Cholecalciferol
(Vitamin D3)
Liver or kidney
1,25-dihydroxyCholecalciferol
Selected food Source for Vitamin D
Food
Cod liver oil, 1 tablespoon
IUs per
serving*
Percent
DV**
1,360
340
Salmon (sockeye), cooked, 3 ounces
447
112
Mackerel, cooked, 3 ounces
388
97
Tuna fish, canned in water, drained, 3 ounces
154
39
Orange juice fortified with vitamin D, 1 cup (check product
labels, as amount of added vitamin D varies)
137
34
115–124
29–31
Yogurt, fortified with 20% of the DV for vitamin D, 6 ounces
(more heavily fortified yogurts provide more of the DV)
88
22
Margarine, fortified, 1 tablespoon
60
15
Liver, beef, cooked, 3.5 ounces
49
12
Sardines, canned in oil, drained, 2 sardines
46
12
Egg, 1 large (vitamin D is found in yolk)
41
10
Ready-to-eat cereal, fortified with 10% of the DV for vitamin D,
0.75–1 cup (more heavily fortified cereals might provide more
of the DV)
40
10
6
2
Milk, nonfat, reduced fat, and whole, vitamin D-fortified, 1 cup
Cheese, Swiss, 1 ounce
* IUs = International Units.
** DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the
nutrient contents among products within the context of a total daily diet.
Vitamin D and Cancer
• Vitamin D has ability to decrease
proliferation of prostate, colon, ovarian and
renal carcinoma as well as lymphoma and
melanoma cells.
• Higher 25(OH)D has a protective effect in
the development of colorectal adenoma and
carcinomas.
• Plasma 25(OH)D was inversely associated
with risk of colorectal and prostate cancer
Among premenopausal women, high intake of vitamin D and
calcium was associated with reduced risk of breast cancer, but
difference between Vitamin D and calcium was not distinguishable.
Summary of literature search
Breast cancer survivors and vitamin
D: A review
Stephanie L. Hines, M.D.a, H. Keels S. Jorn, M.D.b, Kristine M. Thompson,
M.D.c, Jan M. Larson, M.D.d
Abstract
Recent evidence has suggested a role for vitamin D in breast cancer prevention
and survival. Studies have reported an inverse relation between vitamin D intake
and the risk of breast cancer, improvements in survival after a diagnosis of breast
cancer in women with higher levels of vitamin D, and vitamin D insufficiency in up
to 75% of women with breast cancer. Preclinical data have indicated that vitamin
D affects up to 200 genes that influence cellular proliferation, apoptosis,
angiogenesis, terminal differentiation of normal and cancer cells, and
macrophage function. Vitamin D receptors have been found in up to 80% of
breast cancers, and vitamin D receptor polymorphisms have been associated
with differences in survival. Although ongoing studies have investigated a
possible link between adequate levels of vitamin D and improved cancer
prognosis, breast cancer survivors may derive additional, non–cancer-related
benefits from adequate vitamin D levels, including improvements in bone mineral
density, quality of life, and mood. Maintaining adequate vitamin D stores is
recommended for breast cancer survivors throughout their lifetime.
Nutr 2010
Suggested Vitamin D Intake by Institute of
Medicine and Endocrine Society
Patient guidance to vitamin D deficiency,
Sources for Natural Vitamin D
• Sun Exposure 10 to 15 min between 9
am to 4 pm
• Avoid Sunscreen protector except on
face
• Foods rich in natural vitamin D
The effect of Vegetables on the
Proliferation of Breast Cancer Cells
Potential foods that may
help against breast cancer
• Brassica vegetables like broccoli,
cauliflower and cabbage
• Linseed/Flaxseed and berries
• Vitamin D rich food
• Fish oil
• Green tea
• Mushroom
The Balance !!
SUMMARY
• Nutritional supplements would be beneficial for cancer
care when they are administered in the right dose, at right
time, and for the right people
• Administration of nutritional supplements should be
limited during chemo- or radiation treatment
• Dietary source of anti-inflammatory and anticancer
phytochemicals would still be preferable comparing to the
concentrated extracts
• More vigorous studies on this particular field are definitely
needed
Resources
• National Cancer Institute (NCI)
http://www.cancer.gov
• National Center for Complementary and
Alternative Medicine (NCCAM)
http://www.nccam.nih.gov
• National Certification Commission for
Acupuncture and Oriental Medicine
(NCCAOM) [Online].
http://www.nccaom.org/om_first.htm
• MD Anderson Cancer Center
http://www.mdanderson.org/cimer
Books
• Anti-cancer - A new way of life, by
David Servan- Schreiber
• Life After Cancer by Keith Block